PROCESS FOR PREPARING CATIONIC RHODIUM COMPLEXES

Description

Background of the Invention

1. Field of the Invention

[0001] This invention relates to an improved process, suitable for operation on a commercial scale, for the preparation of cationic rhodium complexes of phosphorus-containing chiral ligands. In particular it relates to the preparation of rhodium complexes used as catalysts for asymmetric synthesis, in particular asymmetric hydrogenation.

2. Description of the Prior Art

[0002] The efficient production of chiral single enantiomer compounds is one of the most important challenges in modem fine chemical and pharmaceutical manufacturing. The asymmetric hydrogenation of substituted olefins by transition metal complexes modified with chiral phosphorus ligands is an exceptionally powerful method of introducing chirality in to a molecule. This is achieved by preferential binding to one face of the olefin by the transition metal/phosphorus ligand complex and subsequent hydrogenation gives rise to a product enriched in one stereoisomer. Asymmetric hydrogenation is particularly suitable to large-scale hydrogenation due to a variety of factors: use of sub-stoichiometric amounts of catalyst, the clean nature of the reaction and the availability of large-scale equipment. Many classes of phosphorus ligands and transition metal complexes have been developed for asymmetric olefin hydrogenation. Amongst the most effective catalysts are cationic rhodium chiral phosphorus ligand complexes. Their particular success is due to their high catalyst activity, productivity and enantioselectivity.

[0003] Fine chemicals and pharmaceutical intermediates hydrogenated by cationic rhodium chiral phosphorus ligand complexes are often complex multifunctional molecules and this complexity is frequently reflected in the requisite chiral phosphorus ligands which are similarly complex in structure and often made via multistep syntheses. As a consequence many of the most effective chiral phosphorus ligands are exceptionally difficult and costly to synthesise and the efficient formation of cationic rhodium phosphine complexes is a critical aspect of the economic viability of an asymmetric hydrogenation catalyst or its subsequent application in hydrogenation processes.

[0004] In principle cationic rhodium chiral phosphorus ligand complexes can be generated in two ways: 1) in-situ by mixing the chiral ligand and a suitable metal precursor or by 2) using a preformed complex. Using an in-situ formed catalyst has several distinct disadvantages: 1) many ligands are very oxygen sensitive and can be readily oxidised by poor handling; 2) in-situ catalyst formation introduces an extra process step; 3) in-situ generation of a catalyst can also give rise inconsistent results; 4) incorrect metal/ligand stoichiometry can adversely effect catalyst activity and selectivity. Such factors may limit applicability in pharmaceutical manufacturing from a regulatory as well as a technical viewpoint. However, use of a preformed complex can overcome these difficulties: 1) complexation of a sensitive ligand by a metal centre can stabilise the ligand; 2) preformed catalysts can be easily handled and introduced into a process avoiding an additional step and 3) a preformed catalyst will be a well defined and characterised species which gives more consistent results.

[0005] As asymmetric hydrogenation catalysts are most often used in the synthesis of high value active pharmaceutical ingredients, pharmaceutical intermediates and other fine chemicals it is of the utmost importance to guarantee the integrity of the catalyst and this can be readily achieved by use of preformed species. However, it is challenging to establish reliable and economic processes to prepare and isolate such cationic rhodium complexes in a form suitable for storage. This point is highlighted by the inability, to date, to form a crystalline cationic rhodium catalyst of adequate storage stability with the commercially available chiral ligand RoPHOS. Isolated solid cationic rhodium catalyst produced from RoPHOS undergoes spontaneous decomposition leading to loss of valuable catalyst and ligand (Conference Proceedings, Chiral Europe 2003, M. Thommen, Solvias AG).

[0006] The numerous chiral phosphorus ligand complexes described in the literature have given rise to a variety of synthetic routes to their corresponding cationic rhodium catalysts. The most common method for the preparation of cationic rhodium phosphorus complexes is the treatment of [(1,5-cyclooctadiene)₂Rh][X] , where X is an anion and typically [BF₄]^-, [PF₆]^-, [SbF₆]^-, [ClO₄]^-, or [OSO2CF₃]^- with a requisite chiral phosphorus ligand. For representative examples see: J. Am. Chem. Soc. 1971, 73, 2397; Helv. Chem. Acta. 1991, 74, 370; Organometallics 2003, 93, 1356; Organometallics 2002, 21, 4611; J. Am. Chem. Soc. 1993, 115, 10125. Where low polarity solvents are used to aid product recovery, inclusion of the metal-precursor in the product is a hazard due to the relative insolubility of [(1,5-cyclooctadiene)₂Rh][X] in low polarity solvents. Contamination of the chiral cationic rhodium catalyst with the achiral metal-precursor can reduce the overall stereoselectivity of the asymmetric hydrogenation. This problem can be overcome by using an excess of ligand, however, where expensive ligands are employed this option is undesirable. Moreover, further reaction of the preformed complex and excess ligand are a possibility giving rise to species less selective than the desired catalyst. Use of [(1,5-cyclooctadiene)₂Rh][X] in more polar solvents such as tetrahydrofuran often requires evaporation, trituration with an anti-solvent and crystallisation steps to obtain pure product.

[0007] In an alternative process, the chlorido precursor [(1,5-cyclooctadiene)RhCl]₂ can be treated with salts such as AgBF₄, AgPF₆, AgClO₄, AgSbF₆, NH₄PF₆, NaBF₄, NaSbF₆ and NaClO₄ to abstract the chloride and treatment with a requisite phosphorus ligand can give rise to a cationic rhodium catalyst. For representative examples see: J. Organometall. Chem. 1999, 577, 346; J. Organometall. Chem. 1983, 251, 79; Helv. Chim. Acta. 1988, 71, 897; Bull. Chem. Soc. Jpn. 1984, 57, 2171; Inorg. Chem. 1980, 19, 577; J. Organometall. Chem. 1982, 239, 1. This route is disadvantageous for large scale applications as silver salts such as AgBF₄ and AgSbF₆ are expensive reagents. Furthermore, the AgCl generated must be removed by filtration before using the catalyst in subsequent reactions. Where salts such as NaBF₄ or NH₄PF₆ are used the chloride salts generated must be removed via an aqueous wash, thus adding additional separation and drying steps to remove salts and water. Also labile ligands such as phosphoramidites, phosphonites and phosphites are unsuitable for this method due to the reactivity towards moisture. Moreover, contamination of the cationic catalyst with chloride can be particularly detrimental to catalyst performance as highlighted by Cobley et al in Organic Process Research & Development 2003, 7, 407.

[0008] In another process where [(1,5-cyclooctadiene)Rh(acetylacetonate)] is treated with aqueous HClO₄, a cationic rhodium catalyst can be generated by addition of an appropriate phosphorus ligand, Inorg. Chem. 1981, 20, 3616. Yields can be variable using this method and also close examination of the reaction liquors by ³¹P-NMR reveals the presence of a variety species other than product thus limiting the maximum yield of the reaction. Use of the aqueous acids such HClO₄ limits the scope of chiral phosphorus ligands applicable in this method. Common chiral phosphorus ligands such as phosphites, phosphonites and phosphoramidites cannot be used with aqueous acids as the reaction conditions applied lead to decomposition of the ligand.

[0009] In a related method Schmutzler (Z. Anorg. Allg. Chem. 2002, 628, 545 and Z. Anorg. Allg. Chem. 2002, 628, 779) has shown direct reaction of [(1,5-cyclooctadiene)Rh(acetylacetonate)] with calixarene derived phosphites and biurets at - 78°C followed by subsequent reaction with ethereal HBF₄ can give rise to cationic rhodium phosphorus complexes, albeit in reduced yield and as an air- and moisture-sensitive form.

[0010] Another method of producing cationic rhodium phosphorus complexes is the reaction of [(norbornadiene)Rh(acetylacetonate)] with Ph₃CBF₄ and a suitable chiral phosphorus ligand, J. Am. Chem. Soc. 1983, 105, 7288. The applicability of this method in the industrial case is low due to the prohibitive cost of the reagent Ph₃CBF₄, furthermore the reaction required a reaction temperature of -78°C and the product was only obtained after concentration, trituration and recrystallisation.

[0011] A common feature of the catalyst preparations described is the need for further manipulation of the crude reaction mixtures to isolate the catalyst. Most catalyst preparations result in a homogeneous solution whereby the catalyst must be precipitated from the reaction mixture by addition of an anti-solvent. Addition of anti-solvents commonly gives rise to rapid precipitation of microcrystalline or amorphous material with large surface areas. This is particularly disadvantageous as microcrystalline and amorphous materials are thermodynamically less stable than crystalline materials and can result in poor storability, poor handling ability and accelerated decomposition of the catalyst. In the industrial case, where catalysts are often purchased or prepared far in advance of their use, poor stability of the catalyst can have deleterious effects on the outcome of manufacturing campaigns and have significant financial implications due to loss of catalysts and compromised selectivities and yields. Often there is a need to recrystallise catalysts isolated via precipitation as the material is microcrystalline and of insufficient purity. This adds a further step and results in a reduced overall yield.

[0012] A manufacturing process for cationic rhodium catalysts that consistently produces high purity, crystalline material with a large range of phosphorus-containing ligands would be particularly advantageous. In contrast to the prior art the process of the present invention meets these requirements for industrial viability.

Summary of the Invention

[0013] The invention comprises a process for the preparation and isolation of a non-amorphous cationic rhodium complex having the formula: [Rh(ligand)_m(diolefin)]⁺ X^-, wherein the ligand is an enantiomerically enriched organic compound possessing one or two ligating phosphorous atoms. The invention has general applicability to phosphorus-containing ligands from a wide variety of structural sub-types.

Detailed Description of the Preferred Embodiments

[0014] The invention comprises a process for preparation and isolation of a non-amorphous cationic rhodium complex of formula (1), wherein ligand represents an enantiomerically enriched organic compound possessing one or two ligating phosphorus atoms, and wherein m = 2 when the ligand is monodentate and m = 1 when the ligand is bidentate, which comprises the following steps: _

(a) Dissolution of Rh(diolefin)(acac) in one or more ethereal solvents;

(b) Addition of a perfluarinated non-mineral acid HX selected from HBF₄, HPF₆, HSbF₆ and CF₃SO₃H and alcohol solvent or alcohol-containing solvent mixture, either simultaneously or sequentially, to form a soluble solvated complex of rhodium with one or more of the reaction solvents;

(c) Addition of the ligand, either in solution in an organic solvent or neat;

(d) Collection of the crystalline precipitate of complex (1).

        [Rh(ligand)_m(diolefin)⁺X^-

[0015] Preferably, step (b) of the process involves simultaneous addition. More preferably, step (b) comprises addition of HX as a solution in an alcohol solvent or alcohol-containing solvent mixture.

[0016] Preferably, the diolefin used in the process is a cyclic diolefin. More preferably, the diolefin is selected from between 1,5-cyclooctadiene (COD) or 2,5-norbomadine (NBD). In the most preferred embodiment, the diolefin is COD. Alternatively, diolefin in formula (1) represents two molecules of an olefin selected from the group consisting of ethylene and C_5-10 cycloalkenes. Most preferably, the fluorinated non-mineral acid HX is HBF_4.

[0017] In the preferred process, the ethereal solvents are selected from the group consisting of dialkyl ethers, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. In the case where dialkyl ethers are used as an ethereal solvent for the process of the invention, they are preferably selected from the group consisting of t-butyl methyl ether, diethyl ether, diisopropyl ether and di-n-butyl ether. Most preferably, the dialkyl ether is t-butyl methyl ether. Under an alternative embodiment, the dialkyl ether is in admixture with tetrahydrofuran. Preferably, the ratio of dialkyl ether:tetrahydrofuran ranges from about 10:1 to about 1:1. More preferably, the ratio of dialkyl ether:tetrahydrofuran ranges from about 6:1 to about 2:1.

[0018] Preferably, the alcohol solvent is a linear or branched C_1-6 alkanol, wherein the alkanol is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, and 1-butanol. In the process of the invention, the organic solution used for dissolution of the ligand is selected from the group comprising ethereal solvents, non-polar hydrocarbon solvents and mixtures thereof.

[0019] In the ligands used in the process of the invention, the ligating phosphorous atom (or atoms) may either be in the form of a tertiary phosphine or may be covalently bonded to one or more heteroatoms. The description below of various embodiments of the invention is provided for! the purpose of illustration, to present representative but nonlimiting examples of suitable ligands. Numerous designs of bidentate and monodentate chiral phosphorus ligands have been reported and this continues to be a highly active area of scientific endeavour. For a recent comprehensive review, see Tang and Zhang, Chem. Rev., 2003, 103, 3029.

[0020] When m = 1 in complex (1) and the ligand is bidentate, in one embodiment of the invention the ligand is a diphosphine. The diphosphine may be a bisphosphacycle, preferably containing either two phospholane rings or two phosphetane rings. In the case of bisphospholanes, a well established class of ligands is represented by general formula (2), or the opposite enantiomer thereof, wherein X represents an organic or organometallic bridging radical, R¹ and R² are each independently H or an optionally substituted hydrocarbon group, provided that R¹ and R² are are not both H, the 3- and 4-positions of either or both phospholane rings optionally may be substituted with one or more non-interfering groups, and each phospholane ring may either be an isolated ring as depicted or embedded in a polycyclic ring system. Preferably, R¹ and R² are each independently C_1-20 alkyl, aryl or aralkyl. More preferably, R¹ = R² = C_1-20 alkyl or R¹ = R² = phenyl. In the case where R¹ = R² = C_1-20 alkyl, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl. The process of the present invention is applicable to in the preparation of complexes (1) in which the ligand is a hydroxylated variant of (2). For this embodiment it can be convenient to use a ligand precursor bearing an acid-labile hydroxyl protecting group, which is cleaved during formation of the rhodium complex.

[0021] The preferred P-X-P bridging radical in the bisphospholane (2) is selected from a group consisting of formulae (3) to (8), each of which may be optionally substituted; n in (4) is in the range 0-5; X in (8) is either O or N-alkyl. More preferably P-X-P is either (3) or (4) in which n is 1. With respect to the backbone structures (3) to (8), it will be readily appreciated by those skilled in the art that through substitution of alternative backbone structures, it may be possible in order to obtain ligands that can be converted to rhodium complexes by the process of the present invention.

[0022] Alternative bisphospholane ligands that convertible to rhodium complexes by the process of the present invention are those containing two stereogenic phosphorus centers, including compound (9), the opposite enantiomer thereof and substituted analogues thereof.

[0023] In the case of bisphosphetanes, a further embodiment of the process of the present invention employs a ligand represented by formula (10), or the opposite enantiomer thereof, wherein X represents an organic or organometallic bridging radical, R¹ and R² are each independently H or an optionally substituted hydrocarbon group, provided that R¹ and R² are are not both H, and the 3-position of either or both phosphetane rings optionally may be substituted with one or more non-interfering groups. Preferably X is 1,1'-ferrocenyl and R¹ and R² are each independently C_1-20 alkyl, aryl or aralkyl. More preferably, R¹ = R² = C_1-20 alkyl or R¹ = R² = phenyl. In the case where R¹ = R² = C_1-20 alkyl, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

[0024] Yet another embodiment of the process of the invention utilizes a diphosphine ligand comprising an atropisomeric diphosphine containing two P(Ar)₂ groups, wherein Ar = phenyl, optionally substituted with one or more alkyl or alkoxy groups. Preferably, the atropisomeric diphosphine is a biaryldiphosphine in which the biaryl moiety may optionally be heteroaromatic. A preferred biaryldiphosphine of the invention is a BINAP ligand of formula (11), or the opposite enantiomer thereof. A representative heteroaromatic analogue is the diphosphine (12), or the opposite enantiomer thereof.

[0025] A further embodiment of the invention comprises a process wherein the diphosphine is a ligand of formula (13), or the opposite enantiomer thereof. Optionally, the [2,2']-paracyclophane backbone of (13) may be further substituted.

[0026] A further embodiment of the invention comprises a process wherein the ligand is a chiral ferrocene-based diphosphine. In addition to the bisphosphetane (10) wherein X = 1,1-ferrocenyl, there are several well established sub-classes of such diphosphines, as described by Tang and Zhang, ibid. The non-C₂-symmetric Josiphos-type ligands of Togni et al. (J. Am. Chem. Soc., 1994, 116, 4062) provide the best known examples.

[0027] When m = 1 in complex (1), at least one of the ligating phosphorus atoms in the ligand may be covalently bonded to one or more heteroatoms. In this embodiment of the invention, preferably both ligating phosphorus atoms are covalently bonded to one or more heteroatoms. More preferably, the ligand is selected from the group consisting of bisphosphites, bisphosphinites, bisphosphonites and bisphosphoramidites.

[0028] Yet another embodiment of the invention comprises a process wherein the ligand is a monophosphine and accordingly m = 2 in complex (1). Preferably, the monophosphine ligand comprises a P-aryl phosphacycle. Still another embodiment of the invention comprises a process wherein the ligand is a phosphoramidite of formula (14), or the opposite enantiomer thereof, and accordingly m = 2 in complex (1)

[0029] Throughout all embodiments of the invention, it is preferred that complex (1) be obtained in a crystalline form and that complex (1) is stable to storage, under an inert atmosphere at ambient temperature, for at least three (3) days. According to the preferred embodiment of the process of the invention, the ligand is enantiomerically enriched to at least 95% ee. More preferably, the ligand is enantiomerically enriched to at least 99% ee. Most preferably, the ligand is enantiomerically pure.

[0030] The following examples illustrate the present invention:

Example 1: Synthesis of ((-)-1,2-Bis-((2R,5R)-2,5-dimethylphospholano)benzene)(1,5-cyclooctadienelrhodium(I) tetrafluoroborate: [((R,R)-MeDuPHOS) Rh (COD)][BF₄]

[0031] A 10 litre jacketed glass vessel fitted with a programmable circulator, contact thermometer, over-head stirrer, reflux condenser, condenser circulator, bottom outlet valve, three addition ports, two membrane dosing pumps and a filter assembly with 10 litre receiver flask was connected to nitrogen/vacuum assembly and placed under an inert nitrogen atmosphere. The reactor was charged with 0.600 kg (1.934 mol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 0.411 kg of degassed tetrahydrofuran and 1.708 kg of degassed t-butyl methyl ether. The reflux condenser temperature was set to 10 °C. The vessel contents were stirred and heated via the programmable circulator to gentle reflux until all material was dissolved. A schlenk flask fitted with a side arm with an inline filter, connected to the reactor via a dosing pump, was charged with 0.726 kg of degassed propan-2-ol, 0.376 kg (2.322 mol) tetrafluoroboric acid diethyletherate was slowly added to the propan-2-ol under stirring whilst maintaining a temperature 35 °C or below. A second schlenk flask with a side arm and an in-line filter, connected to the reactor via a second membrane pump, was charged with 1.069 kg of degassed tetrahydrofuran and 0.593 kg (1.935 mol) of ((-)-1,2-bis((2R,5R)-2,5-dimethylphospholano)benzene) under stirring until all material had dissolved. The propan-2-ol solution of tetrafluoroboric acid diethyletherate was added continuously over 25 minutes to the reactor vessel, whist maintaining a gentle reflux, using a membrane dosing pump to give a transparent yellow/brown homogenous solution. The dosing pump line was rinsed with 3 × 20 ml of degassed propan-2-ol and the reactor contents stirred at reflux for approximately ∼20 minutes. The solution of ((-)-1,2-bis((2R,5R)-2,5-dimethylphospholano)benzene) in degassed tetrahydrofuran was added continuously over ∼22 minutes using a membrane dosing pump, whilst maintaining gentle reflux, and the pump lines rinsed with 3 × 20 ml or degassed tetrahydrofuran. Addition of the ((-)-1,2-bis((2R,5R)-2,5-dimethylphospholano)benzene) solution caused almost instant precipitation of deep red crystalline product. After addition of the ((-)-1,2-bis((2R,5R)-2,5-dimethylphospholano)benzene) solution was complete the vessel contents were stirred at reflux for ∼ 26 mins before programming the vessel circulator to cool to ∼-25 °C over six hours in a linear fashion. The vessel contents were transferred to the filter assembly under N₂ via the bottom outlet valve under a N₂ pressure. The reactor and the filter assembly were rinsed twice via the vessel with 2 × 1.25 kg of degassed propan-2-ol and the residual solvent removed under vacuum. The filter cake was finally rinsed with 3 × 0.384 kg of a degassed 3:2 tetrahydrofuran/t-butyl methyl ether solution and vacuum dried to constant weight. The reaction yielded 1.102 kg, 94.3% of ((-)-1,2-bis((2R,5R)-2,5-dimethylphospholano)benzene)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ77.1 ppm, doublet, J_Rh-P 148.6 Hz

Example 2: Synthesis of ((-)-1,2-Bis-((2R,5R)-2,5-diethylphospholano)benzene)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [((R,R)-EtDuPHOS) Rh (COD)][BF₄]

[0032] A schlenk flask under nitrogen was charged with 1.5988 g (5.154 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 1.239 g dry, degassed tetrahydrofuran and 6.147 g of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 1.001 g (6.1848 mmol) of tetrafluoroboric acid diethyletherate in 1.918 g of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 20 mins. A solution of 1.8687 g (5.154 mmol) (-)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene in 7.400 g of degassed t-butyl methyl ether was added dropwise over 10 minutes to give a red crystalline precipitate. The reaction was stirred for a further 20 minutes before cooling to -20 °C. The reaction solvent was removed via syringe and the material washed with 2 × 1.48 g degassed t-butyl methyl ether and dried under vacuum to give 3.211 g, 97 % yield of ((-)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ70.4 ppm, doublet J_Rh-P 148.7 Hz

Example 3: synthesis of ((+)-1,2-Bis-((2R,SR)-2,5-dimethylphospholano)ethane)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [((R,R)-MeBPE) Rh (COD)][BF₄]

[0033] A schlenk flask under nitrogen was charged with 6.00 g (19.356 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 4.656 g dry, degassed tetrahydrofuran and 23.082 g of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 3.76 g (23.22 mmol) of tetrafluoroboric acid diethyletherate in 7.20 g of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 20 mins. A solution of 5 g (19.356 mmol) of 1,2-bis-((2R,5R)-2,5-dimethylphospholano)ethane in 22.2 g of degassed t-butyl methyl ether was added dropwise over 20 minutes to give an orange/red crystalline precipitate. The reaction was stirred for a further 20 minutes before cooling to -20 °C. The reaction was filtered under nitrogen and dried under vacuum to give 10.19 g, 96.4 % yield of (1,2-bis-((2R,5R)-2,5-dimethylphospholano)ethane)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ77.49 ppm, doublet J_Rh-P 144.7 Hz

Example 4: synthesis of (1,2-Bis-((2S,5S)-2,5-diphenylphospholano)ethane)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [((R,R)-PhBPE) Rh (COD)][BF₄]

[0034] A schlenk flask under nitrogen was charged with 340 mg (1.096 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 445 mg dry, degassed tetrahydrofuran and 2.59 g of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 214 mg (1.322 mmol) of tetrafluoroboric acid diethyletherate in 392 mg of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 30 mins. A solution of 556 mg (1.0975 mmol) of 1,2-bis-((2S,5S)-2,5-diphenylphospholano)ethane in 4.445 g of degassed tetrahydrofuran was added dropwise over 10 minutes to give an orange crystalline precipitate. The reaction was stirred for a further 30 minutes before cooling to room temperature. The reaction was filtered under nitrogen and the material washed with 3.925 g degassed propan-2-ol, 8.89g degassed tetrahydrofuran and dried under vacuum to give 860 mg, 97.5 % yield of (1,2-bis-((2S,5S)-2,5-diphenylphospholano)ethane)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ79.64 ppm, doublet J_Rh-P 153.9 Hz

Example 5: synthesis of (1,1'-Bis-((2R,5R)-2,5-diisopropylphospholano)ferrocene)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [((R,R)-i-Pr-5-Fc) Rh (COD)][BF₄]

[0035] A schlenk flask under nitrogen was charged with 200 mg (0.6448 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 155 mg dry, degassed tetrahydrofuran and 769 mg of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 125 mg (0.7719 mmol) of tetrafluoroboric acid diethyletherate in 240 mg of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 20 mins. A solution of 338.2 mg (0.6448 mmol) of 1,1'-bis((2R,5R)-2,5-diisopropylphospholano)ferrocene in 1.48 g of degassed t-butyl methyl ether was added dropwise over 10 minutes to give an orange crystalline precipitate. The reaction was stirred for a further 10 minutes before cooling to -20 °C. The reaction solvent was removed via syringe and the material washed with 2 × 1.48 g degassed t-butyl methyl ether and dried under vacuum to give 507 mg, 96.9 % yield of (1,1'-bis((2R,5R)-2,5-diisopropylphospholano)ferrocene)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ30.3 ppm, doublet J_Rh-P 141.2 Hz

Example 6: synthesis of ((+)-1,1'-Bis-((2R,4R)-2,4-diethylphosphetano)ferrocene)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [((R,R)-EtFerroTANE) Rh (COD)][BF₄]

[0036] A schlenk flask under nitrogen was charged with 3.522 g (11.355 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 2.729 g dry, degassed tetrahydrofuran and 13.541 g of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 2.206 g (13.626 mmol) of tetrafluoroboric acid diethyletherate in 4.225 g of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 20 mins. A solution of 5 g (11.355 mmol) of (+)-1,1'-bis-((2R,4R)-2,4-diethylphosphetano)ferrocene in 14.80 g of degassed t-butyl methyl ether was added dropwise over 10 minutes to give an orange crystalline precipitate. The reaction was stirred for a further 20 minutes before cooling to -20 °C. The reaction was filtered under nitrogen and dried under vacuum to give 7.55 g, 91 % yield of ((+)-1,1'-bis-((2R,4R)-2,4-diethylphosphetano)ferrocene)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ51.74 ppm, doublet J_Rh-P 146.4 Hz

Example 7: synthesis of ((R)-(+)-2,2'-Bis-(diphenylphosphino)-1,1'-binaphthyl)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [((R)-BINAP) Rh (COD)][BF₄]

[0037] A schlenk flask under nitrogen was charged with 100 mg (0.322 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 68.5 mg dry, degassed tetrahydrofuran and 384.7 mg of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 62.6 mg (0.387 mmol) of tetrafluoroboric acid diethyletherate in 120 mg of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 20 mins. A solution of 200.6 mg (0.322 mmol) (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in 0.889 g of degassed tetrahydrofuran and 2.2 g of degassed t-butyl methyl ether was added dropwise over 10 minutes to give an orange/red crystalline precipitate. The reaction was stirred for a further 20 minutes before cooling to -20 °C. The reaction solvent was removed via syringe and the material washed with 2 × 1.48 g degassed t-butyl methyl ether and dried under vacuum to give 292 mg, 99 % yield of ((R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ26.6 ppm, doublet J_Rh-P 146.8 Hz

Example 8: synthesis of ((R)-(-)-4,12-Bis-(diphenylphoshino)-[2.2]-paracyclophane)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [((R)-PhanePhos) Rh (COD)][BF₄]

[0038] A schlenk flask under nitrogen was charged with 50 mg (0.1612 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 34.25 mg dry, degassed tetrahydrofuran and 192.4 mg of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 31.3 mg (0.1934 mmol) of tetrafluoroboric acid diethyletherate in 60 mg of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 25 mins. A solution of 92.95 mg (0.1612 mmol) (R)-(-)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane in 1.78 g of degassed tetrahydrofuran and 2.2 g of degassed t-butyl methyl ether was added dropwise over 10 minutes to give an orange/red crystalline precipitate. The reaction was stirred for a further 20 minutes before cooling to -20 °C. The reaction solvent was removed via syringe and the material washed with 2 × 1.48 g degassed t-butyl methyl ether and dried under vacuum to give 134 mg, 95 % yield of ((R)-(-)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ33.3 ppm, doublet J_Rh-P 147 Hz

Example 9: synthesis of (Bis-((R)-(-)-(3,5-Dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)dimethylamine))(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [((R)-Monophos)₂ Rh (COD)][BF₄]

[0039] A schlenk flask under nitrogen was charged with 100 mg (0.322 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 68.5 mg dry, degassed tetrahydrofuran and 384.7 mg of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 62.6 mg (0.387 mmol) of tetrafluoroboric acid diethyletherate in 120 mg of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 20 mins. A solution of 231.6 mg (0.644 mmol) (R)-(-)-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)dimethylamine in 1.33 g of degassed tetrahydrofuran and 2.2 g of degassed t-butyl methyl ether was added dropwise over 10 minutes to give an orange/yellow crystalline precipitate. The reaction was stirred for a further 20 minutes before cooling to -20 °C. The reaction solvent was removed via, syringe and the material washed with 2 × 1.48 g degassed t-butyl methyl ether and dried under vacuum to give 281 mg, 87 % yield of (bis-((R)-(-)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)dimethylamine))(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ138 ppm, broad doublet of multiplets

Example 10: synthesis of ((R)-2,2',6,6'-Tetramethoxy-4,4'-bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [(CTH-(R)-Xylyl-P-Phos) Rh (COD)][BF₄]

[0040] A Schlenk flask under nitrogen was charged with 42 mg (0.135 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 100 µl dry, degassed tetrahydrofuran and 200 µl of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 18 µl (0.132 mmol) of tetrafluoroboric acid diethyletherate in 100 µl of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 25 mins. A solution of 102 mg (0.135 mmol) ((R)-2,2',6,6'-Tetramethoxy-4,4'-bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine) in 0.5 ml of degassed tetrahydrofuran and 2 ml of degassed t-butyl methyl ether was added dropwise over 30 minutes to give an orange/red crystalline precipitate. The reaction was stirred for a further 20 minutes before cooling to room temperature. A further 8 ml of degassed t-butyl methyl ether was added dropwise The mixture was cooled to -20 °C, the reaction solvent was removed via syringe and the material was dried under vacuum to give 66 mg, 46 % yield of ((R)-2,2',6,6'-Tetramethoxy-4,4'-bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ 24.7 ppm, doublet J_Rh-P 143 Hz

Example 11: synthesis of ((1S,1S,2R,2R')-1,1'-Di-t-butyl-[2,2']diphospholane)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate: [((S,S,R,R)-TangPhos) Rh (COD)][BF₄]

[0041] A Schlenk flask under nitrogen was charged with 121 mg (0.395 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 300 µl dry, degassed tetrahydrofuran and 600 µl of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 54 µl (0.397 mmol) of tetrafluoroboric acid diethyletherate in 100 µl of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 25 mins. A solution of 113 mg (0.135 mmol) (1S,1S,2R,2R'-1,1'-Di-t-butyl-[2,2']diphospholane in 1 ml of degassed tetrahydrofuran and 2 ml of degassed t-butyl methyl ether was added dropwise over 1 h to give an orange/red crystalline precipitate. The reaction was stirred for a further 20 minutes before cooling to room temperature then cooling in an ice water bath. The product was collected in a Schlenk filter and washed with a further 2 x 2 ml of degassed t-butyl methyl ether. The material was dried under vacuum to give 166 mg, 72 % yield of ((1S,1S",2R,2R')-1,1'-Di-t-butyl-[2,2']diphospholane)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, CDCl₃) δ 97.7 ppm, doublet J_Rh-P 143 Hz

Example 12: synthesis of {(1,2-Bis[(2S,5S)-2,5-dimethyl-(3S,4S)-3,4-dihydroxyphosphalano]benzene}(1,5-cyclooctadiene)rhodium(I) tetafluoroborate, with in-situ deprotection of the ligand precursor.

[0042] A Schlenk flask under nitrogen was charged with 70 mg (0.226 mmol) of (1,5-cyclooctadiene)(acetylacetonato)rhodium (I), 200 µl dry, degassed tetrahydrofuran and 400 µl of degassed t-butyl methyl ether and heated to 55 °C under stirring until all the material dissolved. A solution of 25 µl (0.13 mmol) of tetrafluoroboric acid diethyletherate in 100 µl of degassed propan-2-ol was added dropwise via syringe over 10 mins to give a homogeneous yellow/brown solution. The resulting solution was stirred for a further 30 mins. A solution of 101 mg (0.224 mmol) (S,S,S,S)-MeKetalPhos in 0.5 ml of degassed tetrahydrofuran and 2 ml of degassed t-butyl methyl ether was added dropwise over 1 h to give an orange/red crystalline precipitate. A further 2 ml of t-butyl methyl ether was added dropwise. The reaction was stirred for a further 60 minutes before cooling to room temperature then cooling in an ice water bath. The supernatant liquid was removed and the residue was dried under vacuum to give the product as a red powder 55 mg, 63 % yield of {(1,2-Bis[(2S,5S)-2,5-dimethyl-(3S,4S)-3,4-dihydroxyphosphalano]benzene}(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate.
³¹P NMR (162 MHz, d₄-MeOH) δ 77.6 ppm, doublet J_Rh-P 152 Hz

Claims

1. A process for preparation and isolation of a non-amorphous cationic rhodium complex of formula (1), wherein ligand represents an enantiomerically enriched organic compound possessing one or two ligating phosphorus atoms, and wherein m = 2 when the ligand is monodentate and m = 1 when the ligand is bidentate, which comprises the following steps:

(a) Dissolution of Rh(diolefin)(acac) in one or more ethereal solvents;

(b) Addition of a perfluorinated non-mineral acid HX selected from HBF₄, HPF₆, HSbF₆ and CF₃SO₃H and alcohol solvent or alcohol-containing solvent mixture, either simultaneously or sequentially, to form a soluble solvated complex of rhodium with one or more of the reaction solvents;

(c) Addition of the ligand, either in solution in an organic solvent or neat;

(d) Collection of the crystalline precipitate of complex (1).

        [Rh(ligand)_m(diolefin)]⁺X^-     (1)

2. A process according to Claim 1, wherein step (b) comprises simultaneous addition of HX and alcohol solvent or alcohol-containing solvent mixture.

3. A process according to Claim 2, wherein step (b) comprises addition of HX as a solution in an alcohol solvent or alcohol-containing solvent mixture.

4. A process according to Claim 1, wherein step (b) comprises sequential addition, in either order, of HX and alcohol solvent or alcohol-containing solvent mixture.

5. A process according to Claim 1, wherein the diolefin is a cyclic diolefin.

6. A process according to Claim 5, wherein the diolefin is either 1,5-cyclooctadiene (COD) or 2,5-norbornadine (NBD).

7. A process according to Claim 6, wherein the diolefin is COD.

8. A process according to Claim 1, wherein diolefin represents two molecules of an olefin selected from the group consisting of ethylene and C_5-10 cycloalkenes.

9. A process according to Claim 1, wherein HX is HBF₄.

10. A process according to Claim 1, wherein HX is HPF₆.

11. A process according to Claim 1, wherein HX is CF₃SO₃H.

12. A process according to Claim 1, wherein ethereal solvents are selected from the group consisting of dialkyl ethers, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethene.

13. A process according to Claim 12, wherein dialkyl ethers are selected from the group consisting of t-butyl methyl ether, diethyl ether, diisopropyl ether and di-n-butyl ether.

14. A process according to Claim 13, wherein a dialkyl ether is in admixture with tetrahydrofuran.

15. A process according to Claim 14, wherein the ratio of dialkyl ether:tetrahydrofuran ranges from about 10:1 to about 1:1.

16. A process according to Claim 15, wherein the ratio of dialkyl ether:tetrahydrofuran ranges from about 6:1 to about 2:1.

17. A process according to Claim 16, wherein the dialkyl ether is t-butyl methyl ether.

18. A process according to Claim 1, wherein the alcohol is a linear or branched C_1-6 alkanol.

19. A process according to Claim 18, wherein the alkanol is selected from the group comprising methanol, ethanol, n-propanol, isopropanol, and 1-butanol.

20. A process according to claim 1, wherein the organic solvent used for dissolution of ligand is selected from the group comprising ethereal solvents, non-polar hydrocarbon solvents and mixtures thereof.

21. A process according to claim 1, wherein m = 1.

22. A process according to claim 21, wherein the ligand is a diphosphine.

23. A process according to claim 22, wherein the diphosphine is a bisphosphacycle.

24. A process according to claim 23, wherein the bisphosphacycle is a bisphospholane.

25. A process according to claim 24, wherein the bisphosphacycle is a bisphospholane according to formula (2), or the opposite enantiomer thereof, wherein X represents an organic or organometallic bridging radical, R¹ and R² are each independently H or an optionally substituted hydrocarbon group, provided that R¹ and R² are not both H, and the 3- and 4-positions of either or both phospholane rings optionally may be substituted with one or more non-interfering groups.

26. A process according to claim 25 wherein P-X-P in the bisphospholane is selected from a group consisting of formulae (3) to (8), each of which may be optionally substituted; n in (4) is in the range 0-5; X in (7) is either O or N-alkyl.

27. A process according to claim 26, wherein P-X-P is of formula (3).

28. A process according to claim 26, wherein P-X-P is of formula (4) and n = 1.

29. A process according to claim 26, wherein P-X-P is of formula (5).

30. A process according to claim 24, wherein the bisphosphacycle is a bisphospholane according to formula (9), the opposite enantiomer thereof and substituted analogues thereof.

31. A process according to claim 23, wherein the bisphosphacycle is a bisphosphetane of formula (10), wherein X represents an organic or organometallic bridging radical, R¹ and R² are each independently H or an optionally substituted hydrocarbon group, provided that R¹ and R² are are not both H, and the 3-position of either or both phosphetane rings optionally may be substituted with one or more non-interfering groups.

32. A process according to claim 31, wherein X is 1,1'-ferrocenyl.

33. A process according any of claims 25-29 or 31-32, wherein R¹ and R² are each independently C_1-20 alkyl, aryl or aralkyl.

34. A process according to claim 33, wherein R¹ = R² = C_1-20 alkyl.

35. A process according to claim 34, wherein alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

36. A process according to claim 33, wherein R¹ = R² = phenyl.

37. A process according to claim 22, wherein the diphosphine is an atropisomeric diphosphine containing two P(Ar)₂ groups, wherein Ar = phenyl, optionally substituted with one or more alkyl or alkoxy groups.

38. A process according to claim 37, wherein the diphosphine is a biaryldiphosphine.

39. A process according to claim 38, wherein the biaryldiphosphine is a BINAP ligand of formula (11), or the opposite enantiomer thereof.

40. A process according to claim 38, wherein the biaryl moiety is heteroaromatic.

41. A process according to claim 37, wherein the diphosphine is a PHANEPHOS ligand of formula (13), or the opposite enantiomer thereof.

42. A process according to claim 21, wherein at least one of the ligating phosphorus atoms in the ligand is covalently bonded to one or more heteroatom.

43. A process according to claim 42, wherein both ligating phosphorus atoms are covalently bonded to one or more heteroatoms.

44. A process according to claim 43, wherein the ligand is selected from the group consisting of bisphosphites, bisphosphinites, bisphosphonites and bisphosphoramidites.

45. A process according to claim 1, wherein m = 2.

46. A process according to claim 45, wherein the ligand is a monophosphine.

47. A process according to claim 46, wherein the phosphine is a P-aryl phosphacycle.

48. A process according to claim 45, wherein the ligating phosphorus atom in the ligand is covalently bonded to one or more heteroatoms.

49. A process according to claim 48, wherein the ligand is a phosphoramidite.

50. A process according to claim 49, wherein the phosphoramidite is of formula (14) or the opposite enantiomer thereof.

51. A process according to claim 1, wherein the complex (1) is prepared directly from a ligand precursor containing one or more acid-labile hydroxyl protecting groups, which are removed during complex formation.

52. A process according to claim 1, wherein the complex (1) is obtained is in a crystalline form.

53. A process according claim 1, wherein the complex (1) is stable to storage, under an inert atmosphere at ambient temperature, for at least three (3) days.

54. A process according the claim 1, wherein the ligand is enantiomerically enriched to at least 95% ee.

55. A process according the claim 54, wherein the ligand is enantiomerically enriched to at least 99% ee.

56. A process according to claim 55, wherein the ligand is enantiomerically pure.

Ansprüche

1. Verfahren zur Herstellung und Isolierung eines nichtamorphen kationischen Rhodiumkomplexes der Formel (1), wobei der Ligand eine enantiomer angereicherte organische Verbindung repräsentiert, die ein oder zwei ligierende Phosphoratome besitzt, und wobei m = 2, wenn der Ligand einzähnig ist, und m = 1, wenn der Ligand zweizähnig ist, wobei das Verfahren die folgenden Schritte umfasst:

(a) Lösen von Rh(diolefin)(acac) in ein oder mehr etherischen Lösungsmitteln;

(b) Zugabe einer perfluorierten nichtmineralischen Säure HX, die ausgewählt ist aus HBF₄, HPF₆, HSbF₆ und CF₃SO₃H, und eines alkoholischen Lösungsmittels oder eines alkoholhaltigen Lösungsmittelgemisches, gleichzeitig oder nacheinander, um einen löslichen solvatisierten Komplex von Rhodium mit einem oder mehreren der Reaktionslösungsmittel zu bilden;

(c) Zugabe des Liganden, entweder in Lösung in einem organischen Lösungsmittel oder pur;

(d) Sammeln des kristallinen Niederschlags von Komplex (1)

        [Rh(Ligand)_m(Diolefin)]⁺X^-     (1)

2. Verfahren nach Anspruch 1, wobei Schritt (b) die gleichzeitige Zugabe von HX und alkoholischem Lösungsmittel oder alkoholhaltigem Lösungsmittelgemisch umfasst.

3. Verfahren nach Anspruch 2, wobei Schritt (b) die Zugabe von HX als Lösung in einem alkoholischen Lösungsmittel oder alkoholhaltigen Lösungsmittelgemisch umfasst.

4. Verfahren nach Anspruch 1, wobei Schritt (b) die sequentielle Zugabe, in beliebiger Reihenfolge, von HX und alkoholischem Lösungsmittel oder alkoholhaltigem Lösungsmittelgemisch umfasst.

5. Verfahren nach Anspruch 1, wobei das Diolefin ein cyclisches Diolefin ist.

6. Verfahren nach Anspruch 5, wobei das Diolefin entweder 1,5-Cyclooctadien (COD) oder 2,5-Norbornadien (NBD) ist.

7. Verfahren nach Anspruch 6, wobei das Diolefin COD ist.

8. Verfahren nach Anspruch 1, wobei Diolefin zwei Moleküle eines Olefins repräsentiert, das ausgewählt ist aus der aus Ethylen und C_5-10-Cycloalkenen bestehenden Gruppe.

9. Verfahren nach Anspruch 1, wobei HX HBF₄ ist.

10. Verfahren nach Anspruch 1, wobei HX HPF₆ ist.

11. Verfahren nach Anspruch 1, wobei HX CF₃SO₃H ist.

12. Verfahren nach Anspruch 1, wobei etherische Lösungsmittel ausgewählt sind aus der aus Dialkylethern, Tetrahydrofuran, 1,4-Dioxan und 1,2-Dimethoxyethen bestehenden Gruppe.

13. Verfahren nach Anspruch 12, wobei Dialkylether ausgewählt sind aus der aus t-Butylmethylether, Diethylether, Diisopropylether und Di-n-butylether bestehenden Gruppe.

14. Verfahren nach Anspruch 13, wobei ein Dialkylether in Beimischung mit Tetrahydrofuran vorliegt.

15. Verfahren nach Anspruch 14, wobei das Verhältnis von Dialkylether:Tetrahydrofuran im Bereich von etwa 10:1 bis etwa 1:1 liegt.

16. Verfahren nach Anspruch 15, wobei das Verhältnis von Dialkylether:Tetrahydrofuran im Bereich von etwa 6:1 bis etwa 2:1 liegt.

17. Verfahren nach Anspruch 16, wobei der Dialkylether t-Butylmethylether ist.

18. Verfahren nach Anspruch 1, wobei der Alkohol ein lineares oder verzweigtes C_1-6-Alkanol ist.

19. Verfahren nach Anspruch 18, wobei das Alkanol ausgewählt ist aus der Methanol, Ethanol, n-Propanol, Isopropanol und 1-Butanol umfassenden Gruppe.

20. Verfahren nach Anspruch 1, wobei das zum Lösen des Liganden verwendete organische Lösungmittel ausgewählt ist aus der etherische Lösungsmittel, nichtpolare Kohlenwasserstofflösungsmittel und Mischungen davon umfassenden Gruppe.

21. Verfahren nach Anspruch 1, wobei m=1.

22. Verfahren nach Anspruch 21, wobei der Ligand ein Diphosphin ist.

23. Verfahren nach Anspruch 22, wobei das Diphosphin ein Bisphosphacycle ist.

24. Verfahren nach Anspruch 23, wobei das Bisphosphacycle ein Bisphospholan ist.

25. Verfahren nach Anspruch 24, wobei das Bisphosphacycle ein Bisphospholan nach Formel (2) oder das entgegengesetzte Enantiomer davon ist, wobei X ein organisches oder metallorganisches Brückenradikal ist, R¹ und R² jeweils unabhängig voneinander H oder eine optional substituierte Kohlenwasserstoffgruppe sind, vorausgesetzt R¹ und R² sind nicht beide H und Stellung 3 und 4 eines oder beider Phospholanringe können optional mit einer oder mehreren nichtstörenden Gruppen substituiert sein.

26. Verfahren nach Anspruch 25, wobei P-X-P in dem Bisphospholan ausgewählt ist aus einer aus den Formeln (3) bis (8) bestehenden Gruppe, die jeweils optional substituiert sein kann; n in (4) im Bereich von 0-5 liegt; X in (7) entweder O oder N-Alkyl ist.

27. Verfahren nach Anspruch 26, wobei P-X-P die Formel (3) hat.

28. Verfahren nach Anspruch 26, wobei P-X-P die Formel (4) hat und n=1.

29. Verfahren nach Anspruch 26, wobei P-X-P die Formel (5) hat.

30. Verfahren nach Anspruch 24, wobei das Bisphosphacycle ein Bisphospholan gemäß Formel (9), das entgegengesetzte Enantiomer davon und substituierte Analoga davon ist.

31. Verfahren nach Anspruch 23, wobei das Bisphosphacycle ein Bisphosphetan der Formel (10) ist, worin X ein organisches oder metallorganisches Brückenradikal repräsentiert, R¹ und R² jeweils unabhängig voneinander H oder eine optional substituierte Kohlenwasserstoffgruppe sind, vorausgesetzt R¹ und R² sind nicht beide H und Stellung 3 eines oder beider Phosphetanringe kann optional mit einer oder mehreren nichtstörenden Gruppen substituiert sein.

32. Verfahren nach Anspruch 31, wobei X 1,1'-Ferrocenyl ist.

33. Verfahren nach einem der Ansprüche 25-29 oder 31-32, wobei R¹ und R² jeweils unabhängig voneinander C₁-₂₀-Alkyl, -Aryl oder -Aralkyl sind.

34. Verfahren nach Anspruch 33, wobei R¹ = R² = C_1-20-Alkyl.

35. Verfahren nach Anspruch 34, wobei Alkyl ausgewählt ist aus der aus Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, sec-Butyl und t-Butyl bestehenden Gruppe.

36. Verfahren nach Anspruch 33, wobei R¹ = R² = Phenyl.

37. Verfahren nach Anspruch 22, wobei das Diphosphin ein atropisomeres Diphosphin mit zwei P(Ar)₂-Gruppen ist, wobei Ar = Phenyl, optional substituiert mit ein oder mehr Alkyl- oder Alkoxygruppen.

38. Verfahren nach Anspruch 37, wobei das Diphosphin ein Biaryldiphosphin ist.

39. Verfahren nach Anspruch 38, wobei das Biaryldiphosphin ein BINAP-Ligand der Formel (11) oder das entgegengesetzte Enantiomer davon ist.

40. Verfahren nach Anspruch 38, wobei die Biarylkomponente heteroaromatisch ist.

41. Verfahren nach Anspruch 37, wobei das Diphosphin ein PHANEPHOS-Ligand der Formel (13) oder das entgegengesetzte Entantiomer davon ist.

42. Verfahren nach Anspruch 21, wobei mindestens eines der ligierenden Phosphoratome in dem Liganden kovalent an ein oder mehr Heteroatome gebunden ist.

43. Verfahren nach Anspruch 42, wobei beide ligierenden Phosphoratome kovalent an ein oder mehr Heteroatome gebunden sind.

44. Verfahren nach Anspruch 43, wobei der Ligand ausgewählt ist aus der aus Bisphosphiten, Bisphosphiniten, Bisphosphoniten und Bisphosphoramiditen bestehenden Gruppe.

45. Verfahren nach Anspruch 1, wobei m = 2.

46. Verfahren nach Anspruch 45, wobei der Ligand ein Monophosphin ist.

47. Verfahren nach Anspruch 46, wobei das Phosphin ein P-Arylphosphacycle ist.

48. Verfahren nach Anspruch 45, wobei das ligierende Phosphoratom in dem Liganden kovalent an ein oder mehr Heteroatome gebunden ist.

49. Verfahren nach Anspruch 48, wobei der Ligand ein Phosphoramidit ist.

50. Verfahren nach Anspruch 49, wobei der Phosphoramidit die Formel (14) hat oder das entgegengesetzte Enantiomer davon ist.

51. Verfahren nach Anspruch 1, wobei der Komplex (1) direkt hergestellt wird aus einem L.igandenvorläufer, der ein oder mehr säurelabile Hydroxylschutzgruppen enthält, die während der Komplexbildung entfernt werden.

52. Verfahren nach Anspruch 1, wobei der Komplex (1) in kristalliner Form erhalten wird.

53. Verfahren nach Anspruch 1, wobei der Komplex (1) mindestens drei (3) Tage in einer inerten Atmosphäre bei Umgebungstemperatur lagerbeständig ist.

54. Verfahren nach Anspruch 1, wobei der Ligand auf mindestens 95% ee enantiomer angereichert ist.

55. Verfahren nach Anspruch 54, wobei der Ligand auf mindestens 99% ee enantiomer angereichert ist.

56. Verfahren nach Anspruch 55, wobei der Ligand enantiomer rein ist.

Revendications

1. Procédé de préparation et d'isolement d'un complexe cationique non-amorphe de rhodium, de formule (1) dans laquelle "ligand" représente un composé organique enrichi en l'un de ses énantiomères et comportant un
ou deux atomes de phosphore servant d'atomes liants, et l'indice m vaut 2 si le ligand est monodenté et 1 si le ligand est bidenté, lequel procédé comporte les étapes suivantes :

a) dissoudre un complexe de formule Rh(dioléfine)(acac) dans un ou plusieurs solvants de type éther ;

b) ajouter un acide non-minéral perfluoré de formule HX, choisi parmi les acides de formule HBF₄, HPF₆, HSbF₆ ou F₃CSO₃H, et un solvant de type alcool ou un mélange solvant contenant un alcool, simultanément ou successivement, pour former un complexe soluble de rhodium, solvaté avec l'un ou plusieurs des solvants réactionnels ;

c) ajouter le ligand, pur ou en solution dans un solvant organique ;

d) et recueillir le précipité cristallin de complexe de formule (1) :

        [Rh(ligand)_m(dioléfine)]⁺ X^-     (1)

2. Procédé conforme à la revendication 1, dans lequel l'étape (b) consiste à ajouter simultanément l'acide de formule HX et un solvant de type alcool ou un mélange solvant contenant un alcool.

3. Procédé conforme à la revendication 2, dans lequel l'étape (b) consiste à ajouter l'acide de formule HX à l'état de solution dans un solvant de type alcool ou un mélange solvant contenant un alcool.

4. Procédé conforme à la revendication 1, dans lequel l'étape (b) consiste à ajouter successivement, dans n'importe quel ordre, l'acide de formule HX et un solvant de type alcool ou un mélange solvant contenant un alcool.

5. Procédé conforme à la revendication 1, dans lequel la dioléfine est une dioléfine cyclique.

6. Procédé conforme à la revendication 5, dans lequel la dioléfine est soit du 1,5-cyclooctadiène (COD), soit du 2,5-norbornadiène (NBD).

7. Procédé conforme à la revendication 6, dans lequel la dioléfine est du COD.

8. Procédé conforme à la revendication 1, dans lequel "dioléfine" représente deux molécules d'une oléfine choisie parmi l'éthylène et les cycloalcènes en C_5-10.

9. Procédé conforme à la revendication 1, dans lequel l'acide HX est de l'acide de formule HBF₄.

10. Procédé conforme à la revendication 1, dans lequel l'acide HX est de l'acide de formule HPF₆.

11. Procédé conforme à la revendication 1, dans lequel l'acide HX est de l'acide de formule F₃CSO₃H.

12. Procédé conforme à la revendication 1, pour lequel les solvants de type éther sont choisis dans l'ensemble formé par les éthers dialkyliques et les tétrahydrofurane, 1,4-dioxane et 1,2-diméthoxy-benzène.

13. Procédé conforme à la revendication 12, pour lequel les éthers dialkyliques sont choisis dans l'ensemble formé par les tertiobutyl-méthyl-éther, diéthyl-éther, diisopropyl-éther et di-n-butyl-éther.

14. Procédé conforme à la revendication 13, dans lequel on se sert d'un éther dialkylique mélangé avec du tétrahydrofurane.

15. Procédé conforme à la revendication 14, dans lequel le rapport de l'éther dialkylique au tétrahydrofurane vaut d'environ 10/1 à environ 1/1.

16. Procédé conforme à la revendication 15, dans lequel le rapport de l'éther dialkylique au tétrahydrofurane vaut d'environ 6/1 à environ 2/1.

17. Procédé conforme à la revendication 16, dans lequel l'éther dialkylique est du tertiobutyl-méthyl-éther.

18. Procédé conforme à la revendication 1, dans lequel l'alcool est un alcanol en C_1-6, à chaîne linéaire ou ramifiée.

19. Procédé conforme à la revendication 18, dans lequel l'alcool est choisi parmi du méthanol, de l'éthanol, du n-propanol, de l'isopropanol et du 1-butanol.

20. Procédé conforme à la revendication 1, dans lequel le solvant organique servant à dissoudre le ligand est choisi dans l'ensemble formé par les solvants de type éther, les solvants non-polaires de type hydrocarbure, et les mélanges de tels solvants.

21. Procédé conforme à la revendication 1, dans lequel l'indice m vaut 1.

22. Procédé conforme à la revendication 21, dans lequel le ligand est une diphosphine.

23. Procédé conforme à la revendication 22, dans lequel la diphosphine est un bis(phosphacycle).

24. Procédé conforme à la revendication 23, dans lequel le bis-(phosphacycle) est un bis(phospholane).

25. Procédé conforme à la revendication 24, dans lequel le bis-(phosphacycle) est un bis(phospholane) de formule (2) ou son énantiomère opposé, dans laquelle formule X représente un fragment pontant organique
ou organo-métallique, R¹ et R² représentent chacun, indépendamment, un atome d'hydrogène ou un groupe hydrocarbyle portant éventuellement un ou des substituant(s), étant entendu que R¹ et R² ne représentent pas tous les deux des atomes d'hydrogène, et que l'un ou l'autre des cycles phospholane,
ou les deux, peut ou peuvent porter en option, en les positions 3 et 4, un ou plusieurs substituants non-interférants :

26. Procédé conforme à la revendication 25, pour lequel le fragment représenté par P-X-P du bis(phospholane) est choisi dans l'ensemble des fragments de formules (3) à (8), chacun de ces fragments pouvant en option porter un ou plusieurs substituants, étant entendu que dans la formule (4), l'indice n vaut de 0 à 5, et que dans la formule (7), X représente soit un atome d'oxygène, soit un groupe alkyl-imino.

27. Procédé conforme à la revendication 26, dans lequel le fragment représenté par P-X-P est un fragment de formule (3).

28. Procédé conforme à la revendication 26, dans lequel le fragment représenté par P-X-P est un fragment de formule (4) où l'indice n vaut 1.

29. Procédé conforme à la revendication 26, dans lequel le fragment représenté par P-X-P est un fragment de formule (5).

30. Procédé conforme à la revendication 24, dans lequel le bis-(phosphacycle) est un bis(phospholane) de formule (9) ou son énantiomère,
ou l'un de leurs analogues de substitution :

31. Procédé conforme à la revendication 23, dans lequel le bis-(phosphacycle) est un bis(phosphétane) de formule (10), dans laquelle X représente un fragment pontant organique ou organo-métallique, R¹ et R² représentent chacun, indépendamment, un atome d'hydrogène ou un groupe hydrocarbyle portant éventuellement un ou des substituant(s), étant entendu que R¹ et R² ne représentent pas tous les deux des atomes d'hydrogène, et que l'un ou l'autre des cycles phosphétane, ou les deux, peut ou peuvent porter en option, en la position 3, un ou plusieurs substituants non-interférants :

32. Procédé conforme à la revendication 31, dans lequel X représente un fragment pontant 1,1'-ferrocényle.

33. Procédé conforme à l'une des revendications 25 à 29, 31 et 32, dans lequel R¹ et R² représentent chacun, indépendamment, un groupe alkyle en C_1-20, aryle ou aralkyle.

34. Procédé conforme à la revendication 33, dans lequel R¹ et R² représentent tous les deux un même groupe alkyle en C_1-20.

35. Procédé conforme à la revendication 34, pour lequel le groupe alkyle est choisi parmi les groupes méthyle, éthyle, n-propyle, isopropyle, n-butyle, isobutyle, s-butyle et t-butyle.

36. Procédé conforme à la revendication 33, dans lequel R¹ et R² représentent tous les deux un groupe phényle.

37. Procédé conforme à la revendication 22, dans lequel la diphosphine est une diphosphine atropoisomère comportant deux groupes symbolisés par P(Ar)₂ où Ar représente un groupe phényle qui peut, en option, porter un ou plusieurs substituants alkyle ou alcoxy.

38. Procédé conforme à la revendication 37, dans lequel la diphosphine est une biaryl-diphosphine.

39. Procédé conforme à la revendication 38, dans lequel la biaryldiphosphine est un ligand de type BINAP de formule (11) ou son énantiomère opposé :

40. Procédé conforme à la revendication 38, dans lequel le fragment biaryle est hétéroaromatique.

41. Procédé conforme à la revendication 37, dans lequel la diphosphine est un ligand de type PHANEPHOS de formule (13) ou son énantiomère opposé :

42. Procédé conforme à la revendication 21, dans lequel au moins l'un des atomes de phosphore liants du ligand est lié par liaison covalente à un ou plusieurs hétéroatomes.

43. Procédé conforme à la revendication 42, dans lequel les deux atomes de phosphore liants du ligand sont liés par liaison covalente à un ou plusieurs hétéroatomes.

44. Procédé conforme à la revendication 43, pour lequel le ligand est choisi dans l'ensemble formé par les bis-phosphites, les bis-phosphinites, les bis-phosphonites et les bis-phosphoramidites.

45. Procédé conforme à la revendication 1, dans lequel l'indice m vaut 2.

46. Procédé conforme à la revendication 45, dans lequel le ligand est une monophosphine.

47. Procédé conforme à la revendication 46, dans lequel la phosphine est un cycle phosphoré qui porte un substituant aryle placé sur un atome de phosphore.

48. Procédé conforme à la revendication 45, dans lequel l'atome de phosphore liant du ligand est lié par liaison covalente à un ou plusieurs hétéroatomes.

49. Procédé conforme à la revendication 48, dans lequel le ligand est un phosphoramidite.

50. Procédé conforme à la revendication 49, dans lequel le phosphoramidite est le composé de formule (14) ou son énantiomère opposé :

51. Procédé conforme à la revendication 1, dans lequel on prépare le complexe de formule (1) directement à partir d'un précurseur de ligand comportant un ou plusieurs groupes hydroxy-protecteurs labiles en milieu acide, qui sont éliminés au cours de la formation du complexe.

52. Procédé conforme à la revendication 1, dans lequel on obtient le complexe de formule (1) sous forme de cristaux.

53. Procédé conforme à la revendication 1, dans lequel le complexe de formule (1) obtenu reste stable pendant au moins trois jours de stockage à température ambiante et sous atmosphère inerte.

54. Procédé conforme à la revendication 1, dans lequel le ligand est enrichi en un énantiomère avec un excès énantiomérique d'au moins 95 %.

55. Procédé conforme à la revendication 54, dans lequel le ligand est enrichi en un énantiomère avec un excès énantiomérique d'au moins 99 %.

56. Procédé conforme à la revendication 55, dans lequel le ligand est énantiomériquement pur.